ORAL BENZODIAZEPINE SELF ADMINISTRATION

申请人摘要： 新型短效苯二氮卓类药物和部分激动剂的介绍 导致了人们对 苯二氮卓类。然而，严格研究影响经济增长的因素 苯二氮卓类药物的增强作用因缺乏 成功地将这些药物确定为口服的增强剂 实验动物。我们已经制定了程序来建立口头的 运送苯二氮卓类药物作为恒河猴的增强剂。苯二氮卓类 天真的猴子拒绝这些药物溶液，而更喜欢水。因此，一个 培训或获取程序是必要的。随着咪达唑仑的消退 程序中使用了增加数量的药物添加到 乙醇溶液(已经用作增强剂)。在第二个 相态乙醇溶液逐渐减少到零，只剩下 咪达唑仑。在这一过程完成后，咪多扎兰作为一种 增强剂。安定使用的程序很简单，安定是 取代咪达唑仑。最近我们已经成功地替换了 咪达唑仑的三唑仑和阿普唑仑。到目前为止，我们有四个 用作增强剂的苯二氮卓类药物(咪达唑仑、安定、三唑仑和 阿普唑仑)。这笔拨款的目的是为了扩大对 口服苯二氮卓类药物的开发与维护 猕猴的增强剂。一个重要的特点是 不同药代动力学和药效学特征的苯二氮卓类药物 将进行检查，看看在增强效果方面是否存在差异。 既往吸毒史在确定药物获得性方面的重要性 将检查加固效果以及 用一种苯二氮卓类替代药物建立补益作用 又一个。剂量的基本变量将被仔细检查 广泛的取值范围和跨苯二氮卓类药物。经济衰退带来的影响 苯二氮卓类受体拮抗剂，氟马西尼，将根据 苯二氮类药物的变化加强了反应。允许 在不同液体之间进行选择是一种严格且通常快速的方法 测定相对补强效果。在本申请中，例如 程序将被用来研究不同浓度的 同样的药物。此外，还将使用累进比率程序来衡量 不同剂量的强化作用。这两个程序的结果 将会被比较。从这些研究中获得的结果将被综合起来 与我们在其他地方的药物研究中获得的结果一致 药理学课程。这项研究的结果将增加 据我们对控制收购的因素的了解，以及 维持苯二氮类药物强化行为。

APPLICANT'S ABSTRACT: The introduction of new short-acting benzodiazepines and partial agonists has led to an increased interest in the reinforcing effects of the benzodiazepines. However, rigorous study of factors influencing the reinforcing effects of benzodiazepines has been limited due to the lack of success in establishing these drugs as orally delivered reinforcers for laboratory animals. We have developed procedures to establish orally delivered benzodiazepines as reinforcers for rhesus monkeys. Benzodiazepine naive monkeys reject these drug solutions and prefer water. Thus, a training or acquisition procedure is necessary. With midazolam a fading procedure was used whereby increasing amounts of drug were added to an ethanol solution (that was already serving as a reinforcer). In the second phase ethanol solution was gradually decreased to zero, leaving only the midazolam. Upon completion of this procedure midozalam functioned as a reinforcer. The procedure used with diazepam was simple, diazepam was substituted for midazolam. Recently we have successfully substituted triazolam and alprazolam for midazolam. At this point we have four benzodiazepines serving as reinforcers (midazolam, diazepam, triazolam & alprazolam). The aim of this grant is to expand the study of the development and maintenance of orally delivered benzodiazepines as reinforcers for rhesus monkeys. An important feature is that benzodiazepines with different pharmacokinetic and pharmacodynamics profiles will be examined to see if there are differences in reinforcing effects. The importance of prior drug history in determining acquisition of reinforcing effects will be examined as well as the procedure of establishing reinforcing effects by substituting one benzodiazepine for another. The fundamental variable of dose will be carefully examined across a broad range of values and across benzodiazepined. The effects of the benzodiazepine receptor antagonist, flumazenil, will be examined in terms of changes in benzodiazepine reinforced responding. Procedures that permit a choice between different liquids are a rigorous and often rapid method for determining relative reinforcing effects. In the present application such procedures will be used to study choices between different concentrations of the same drug. Also, a progressive ratio procedure will be used to measure reinforcing effects of different doses. The results of the two procedures will be compared. Results obtained from these studies will be integrated with the results we have obtained in studies of drugs from other pharmacological classes. The results of this research will add substantially to our knowledge of factors controlling the acquisition and maintenance of benzodiazepine reinforced behavior.